Sustained release formulations are designed to release a single dose of a pharmacologically active substance at a predetermined rate in order to maintain the effective plasma concentration of the substance in blood stream for a specific period of time, with minimization of the side effects caused by multiple doses.
PLGA [poly(lactic-co-glycolic acid)] is a representative of the currently used biodegradable materials which are approved for use in sustained release by the Food and Drug Administration (FDA). U.S. Pat. No. 5,480,656 reported the sustained release of a pharmacologically active substance by way of the degradation of PLGA into lactic acid and glycolic acid over a specific period of time in vivo. However, the acidic degradation products of PLGA induce inflammation, decreasing cell growth (K. Athanasiou, G. G. Niederauer and C. M. Agrawal, Biomaterials, 17, 93 (1996)).
For the sustained release, PLGA solid particles of 10˜100 micrometers in diameter, including a drug therein must be injected. The injection of the PLGA solid particles is accompanied by pain or inflammation, because the solid particle of 10˜100 micrometers in diameter should be applied through sc or im injection and is degraded over a period of up to several months in injection site. There is therefore a need for a novel sustained release formulation that supplies the effective plasma concentration of a pharmacologically active substance for a prolonged period of time with improved patient compliance.
Culminating in the present invention, intensive and thorough research of the present inventors into the sustained release formulation led to the findings that a lipid pre-concentrate comprising a) a sorbitan unsaturated fatty acid ester having a polar head with at least two or more —OH (hydroxyl) groups; b) a phospholipid; and c) a liquid crystal hardener, free of an ionizable group, having a hydrophobic moiety of 15 to 40 carbon atoms with a triacyl group or a carbon ring structure, exists as a liquid state in the absence of aqueous fluid and transits into a gel-like liquid crystal upon exposure to aqueous fluid, showing an excellent sustained release profile, and that the pre-concentrate is safe to the body and highly biodegradable.
A description is given of the prior arts relevant to the present invention, infra.
International Patent Publication No. WO 2005/117830 describes a pre-formulation comprising a low viscosity, non-liquid crystalline, mixture of: at least one neutral diacyl lipid and/or at least one tocopherol, at least one phospholipid, and at least one biocompatible, oxygen-containing, low viscosity organic solvent. International Patent Publication No. WO 2006/075124 discloses pre-formulations of a low viscosity mixture containing at least one diacyl glycerol, at least one phosphatidyl choline, at least one oxygen-containing organic solvent, and at least one somatostatin analogue. All these pre-formulations release the pharmacologically active materials in vivo for two weeks or longer, but the use of a diacyl lipid, a component essential for the pre-formulations, as a pharmaceutical excipient is not usable and it has to be proven to be sufficiently safe. Another difference with the present invention is that the organic solvents used in the publications are found to decrease the activity of some drugs (H. Ljusberg-Wahre, F. S. Nielse, 298, 328-332 (2005); H. Sah, Y. bahl, Journal of Controlled Release 106, 51-61(2005)).
U.S. Pat. No. 7,731,947 discloses a composition comprising: a particle formulation comprising an interferon, sucrose, methionine, and a citrate buffer, and a suspending vehicle comprising a solvent such as benzyl benzoate, wherein the particle formulation is dispersed in the suspending vehicle. In one Example, it is described that phosphatidylcholine is dissolved together with vitamin E (tocopherol) in an organic solvent and is used to disperse the particle formulation therein. However, this composition is different from the transparent and filterable solution formulation of the present invention in that the composition is used to disperse solid particles and does not allow the formation of liquid crystals.
U.S. Pat. No. 7,871,642 discloses a method of preparing a dispersion for delivering a pharmacologically active agent, comprising dispersing a homogeneous mixture of a phospholipid, a polyoxyethylene coemulsifier, triglyceride and ethanol in water, wherein the polyoxyethylene coemulsifier is selected from among polyethoxylated sorbitan fatty acid esters (polysorbate) and polyethoxylated vitamin E derivatives. Polyethoxylated sorbitan fatty acid esters and polyethoxylated vitamin E derivatives, derived by conjugating the hydrophilic polymer polyoxyethylene to sorbitan fatty acid ester and vitamin E, respectively, are quite different in structure from sorbitan fatty acid ester and vitamin E. They are usually used as hydrophilic surfactants utilizing the property of polyoxyethylene, which is different from the component of the present invention.
U.S. Pat. No. 5,888,533 discloses a flowable composition for forming a solid biodegradable implant in situ within a body, comprising: a non-polymeric, water-insoluble, biodegradable material; and a biocompatible, organic solvent that at least partially solubilizes the non-polymeric, water-insoluble material and is miscible or dis-persible in water or body fluids, and capable of diffusing-out or leaching from the composition into body fluid upon placement within a body, whereupon the non-polymeric material coagulates or precipitates to form the solid implant. In this composition, sterols, cholesteryl esters, fatty acids, fatty acid glycerides, sucrose fatty acid esters, sorbitan fatty acid esters, fatty alcohols, esters of fatty alcohols with fatty acids, anhydrides of fatty acids, phospholipids, lanolin, lanolin alcohols, and mixtures thereof are described as the non-polymeric material, and ethanol is used as the solvent. However, differences from the present invention reside in that this composition cannot form liquid crystals and is designed to form solid implants by simple coagulation or precipitation of water-insoluble materials and that a lot of the organic solvent is necessarily used.